PROJECT SUMMARY Neuropsychiatric diseases such as obsessive-compulsive disorder (OCD), schizophrenia and autism affect 1-3% of the population and cause significant morbidity. Understanding the underlying pathophysiology of these disorders would represent a significant step forward towards developing novel therapeutics for these patients. Human imaging studies from patients and animal models of OCD, autism and schizophrenia have linked dysfunction of the part of the brain called the striatum to the symptoms of these diseases. The striatum is primarily composed of medium-sized spiny neurons (MSNs) which maintain a hyperpolarized resting potential and low firing rate. Before adolescence, MSNs, however, are hyperexcitable and transition postnatally to their adult phenotype. Interestingly, in animal models of schizophrenia and Parkinson's disease, in which dopamine is absent in the striatum, MSNs remain hyperexcitable in adulthood. This suggests that the developmental acquisition of the adult MSN electrical phenotype may be critical to striatal function in the adult and its failure to mature may lead to neuropsychiatric diseases such as OCD, schizophrenia and autism. Nevertheless, little is known about the mechanisms underlying the developmental transitions that occur in MSN electrical properties. Here, I propose to investigate the cell-extrinsic and intrinsic mechanisms that control maturation of MSN excitability during adolescence. In Preliminary Data, I show that MSN excitability dramatically decreases during adolescence as current through inwardly rectifying potassium channels (Kir) increases. Remarkably, despite the increase in Kir current during adolescence, Kir protein decreases. I show that in a mouse which lacks macorautophagy, a process used to degrade synaptic receptors in the CNS, in MSNs, MSN excitability is not reduced during adolescence and Kir protein levels fail to go down. In Aim 1, I propose to investigate the mechanisms through which Kir proteins levels change during adolescence in the striatum, whether this is regulated by macroautophagy and why increased Kir protein at young ages is associated with reduced Kir currents. In Aim 2, I propose to investigate whether cell-extrinsic cues, such as a dopamine, induce changes in MSN excitability during adolescence. The proposal outlined here will use novel transgenic mouse models, electrophysiological and biochemical techniques to address an important question in striatal physiology, with implications for neuropsychiatric disease.